Immunization through topical application without physical penetration by needles has been proved to be effective in eliciting protective immune responses. This novel vaccination modality could potentially immunize a large population of diversified age and health status within a short timeframe during a bioterrorism attack. We are developing a skin-applied, adenovirus (Ad)-vectored anthrax vaccine. One of the problems encountered in using Ad as the vector for skin-applied DNA vaccines is its low efficiency in transducing antigen presenting cells. Ad infection depends on the expression of Coxsackie-adenovirus receptor (CAR) on the surface of its target cells. The limited expression of CAR by Langerhans cells (LC), the principal antigen capture cells in the skin, greatly hindered Ad vector entry and minimized the encoded antigen gene expression. We hypothesize that modifying Ad vector with enhanced tropism for LC could facilitate Ad entry into LC and greatly increase the antigen gene expression, and thereby more effectively mobilize the immune system and amplify the magnitude of host immune responses. Ad vectors with selective tropism for LC will be developed by coating the Ad fiber with LC-targeted ligands. Potency of the new vector will be rigorously examined by inoculation via both a patch and a syringe needle, and compared to that of a spore-based anthrax vaccine.